A variety of devices have been disclosed in the art which provide for the release of an agent, into a fluid medium over a prolonged period of time. Often the agent is a beneficial agent, such as a drug or medicament, which is to be released in the body of a living being. For example, U.S. Pat. No. 3,279,996, issued to Long et al., discloses a method and means for the controlled release of a therapeutic agent into a living organism by implanting within the body of that organism a capsule formed of silicone rubber and containing a therapeutic agent soluble in the rubber and capable of diffusing through the rubber to its outer surface at a constant rate. U.S. Pat. No. 3,993,072, issued to Zaffaroni, discloses a device which comprises a wall surrounding a reservoir containing a drug. The reservoir contains a solid drug carrier which contains the drug of interest. The wall is formed of a microporous material having a plurality of micropores and formed with diffusional conduits throughout. The pores of the wall contain a drug release rate controlling medium which is also permeable to the drug. Another patent, U.S. Pat. No. 3,845,770, issued to Theeuwes et al., is directed to an osmotic device for the controlled release of an agent which comprises a semi-permeable membrane that surrounds a compartment which contains the agent. The wall is permeable to an external body fluid but impermeable to the agent and has a passageway for delivering the agent to the body. To release the agent, fluid is imbibed through the wall into the compartment to produce a solution of the agent. That solution is dispensed through the passageway at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall of the device.
Also of interest is U.S. Pat. No. 4,320,759, issued to Theeuwes, which discloses a device which comprises a microporous wall which surrounds a compartment having a space which contains a beneficial agent separated by a partition from a space which contains an expandable entity, either a swellable polymer or an osmotically effective solute. With this device, an agent is delivered by fluid diffusing through the microporous wall into the space containing the expandable entity causing that space to swell and expand against the partition, urging it to move into the other compartment and maintain the agent in a saturated state. The agent diffuses through fluid-filled paths in the microporous wall.
Despite these and various other systems and devices for releasing beneficial agents, certain problems have remained. For instance, there are times when it would be desirable to deliver two or more agents together from the same device. If the two agents have different rates of diffusion through the porous membrane of the device, however, the delivery can be difficult to effect, especially if it also is desired that the delivery extend over a prolonged period of time.
For example, certain beneficial agents, such as some proteins, when placed in conventional delivery systems, tend to form insolubles and lose their bioactivity upon extended exposure to aqueous environments. In U.S. Pat. No. 4,439,181, issued to Blackshear, the disclosure was made that in some instances precipitation of a protein (insulin in this instance) within the delivery system can be prevented, or at least substantially decreased, by adding an effective amount of a compound that solubilizes the protein and inhibits the action of precipitation agents.
More recently, commonly assigned U.S. Pat. No. 4,816,568 discloses the stabilization of growth hormone by adding various low molecular weight stabilizers. It has been found that a mixture of the stabilizer and growth hormone can be pelletized, placed in a slow release diffusion delivery device, and used as an implant. Further improvements are sought in this system, however, for the stabilizing additive, having a much smaller molecular weight and size than the protein, has a tendency to diffuse out of the device at a much faster rate than the protein. Once the additive is gone, the protein again is subject to wetting problems and aggregation.
There thus remains a need for a device that can deliver for a sustained period of time two or more agents which have different rates of diffusion. It furthermore would be beneficial to have such a device capable of releasing the agents at a substantially steady rate over time.
Accordingly, it is an object of this invention to provide a delivery device for dispensing agents into a fluid medium which overcomes the disadvantages found in devices of the prior art.
It also is an object of the present invention to provide such a device wherein the rate of release of the agents approaches zero order and the agents are released over a prolonged period of time.
It is a further object of this invention to provide such a delivery system in a variety of sizes and shapes and in form suitable for placement within the body of a living being, as by oral ingestion, implantation into body tissues or insertion into a body cavity.
Additional objects of the present invention shall become apparent to those skilled in the art from the description of the invention below taken in conjunction with the accompanying claims and figures.